The Stickler Syndromes Martin Snead Vitreoretinal Service & Vitreoretinal Research Group Addenbrooke’s Hospital Cambridge UK Stickler syndromes form part of the spectrum of Type II/XI collagenopathies Congenital myopia.
Download ReportTranscript The Stickler Syndromes Martin Snead Vitreoretinal Service & Vitreoretinal Research Group Addenbrooke’s Hospital Cambridge UK Stickler syndromes form part of the spectrum of Type II/XI collagenopathies Congenital myopia.
The Stickler Syndromes Martin Snead Vitreoretinal Service & Vitreoretinal Research Group Addenbrooke’s Hospital Cambridge UK Stickler syndromes form part of the spectrum of Type II/XI collagenopathies Congenital myopia (short-sight) High risk of retinal detachment Commonest inherited cause of retinal detachment. Commonest cause of rhegmatogenous retinal detachment in children. Arthropathy: joint laxity and premature arthritis Midline clefting Deafness Midfacial hypoplasia and micrognathia Early, accurate diagnosis essential Poor Visual prognosis in young children Present late (with advanced PVR) or at incidental examination Or worse, only after second eye involvement Clinical features HAO Ocular: High myopia (short sight), Cataract, Retinal detachment: 80%, most bilateral Aural: Deafness Oro-facial: Cleft palate, flat face Articular: Hypermobility, premature arthropathy Healthy compact vitreous Type 1 Stickler syndrome COL2A1 gene 12q13 Type 2 Stickler syndrome COL11A1 gene 1p21 Orofacial midline cleft high arch palate malar hypoplasia nasal hypoplasia Auditory cleft - serous otitis media - conductive loss (grommets) sensorineural loss high tone Hearing loss type 1 Stickler syndrome Reduced hearing Adult 38%, child 51% SNHL in 50-60% mild – moderate, High frequency, Not progressive Conductive hearing loss Frequent ear infections Adult 25%, child 38% Webb and Markus (2002) Admiraal et al. (2002) Skeletal Laxity Premature arthropathy Radiology Radiology in Childhood • Large epiphyses • Overtubulation of long bones • Rhizomelic limb shortening • Femoral epiphyses flattened and irregular • Broad metaphyses • Spine: irregular platyspondyly and anterior wedging “Ocular only” Stickler Syndrome: Molecular Mechanisms (I) 2 1 1 2 3 Type II A Vitreous 3 4 // 4 & Exons 5 - 54 54 1 3 4 & Exons 5 - 54 Type II B Cartilage Richards et al Br. J. Ophthalmol., (2000), 84, 364 – 371 Donoso et al AJO (2002), 134, 720 – 727 “Ocular only” Stickler Syndrome: Molecular Mechanisms (II) transcription NH2….Gly-X-Y-Gly-X-Y-Gly-X-Y-Gly-X-Y-Gly-X-Y…..COOH trimerisation Richards et al Am. J. Hum. Gent. (2000) 67, 1083 – 1094 MS25 I 1 2 II 3 1 2 1 5 6 4 3 7 4 5 9 5 6 10 III IV 1 2 4 21007 20998 20996 C-T 20988 20982 T- Reaction High myopia, Radiology normal, No cleft palate, Hearing normal 70% Detachment in untreated individuals “Ocular only” Stickler Syndrome: Molecular Mechanisms (III) intron exon 5’…AG gta/gagt…………. exon branch point site nc ag 20-50nt G…3’ Three different mutations that altered a specific donor splice site in intron 51 were detected One of the three families affected exhibited a predominantly “ocular-only” phenotype Investigated in more detail as a novel (third) molecular mechanism for “ocular only” Stickler syndrome Amplify region of gene containing a mutation. Transfect DNA into various human cultured cells M EcoRI-ATG N KpnI Confirm complete cloned sequence E K M pCDNA3.1 N Transform into Bacteria Clone into Expression Vector N M M M N N M Normal and Mutant Clones N Correctly spliced in cartlilage Cartilage Ocular Is blindness in Stickler Symdrome avoidable? Propensity for Giant Retinal Tear Bilateral Retinal detachment in Stickler Syndrome Common (60 – 80%) Frequently affects both eyes Any age (18 months – 80yr) Poor prognosis in young children present late or at incidental examination second eye involvement Blindness combined with deafness and speech difficulties and arthropathy Type 1 Stickler Syndrome (n=204) • GROUP 1: Control patients: No prophylactic treatment to either eye (n=111) • GROUP 2: Study patients: Received 360 degree contiguous prophylactic cryotherapy to both eyes (n=62) • GROUP 3: Mixed: Patients who presented to us with a detachment in their first or “control” eye for repair and underwent prophylactic treatment to their second or “study” eye. (n=31) Follow up Study Group (62): Mean follow up 11.5yr (1-27yr) Mixed Group (31): Mean follow up 15.5yr (1-33yr) RESULTS OF PROPHYLAXIS Untreated 83% Detached 66% Bilateral Treated 97% No Detachment 3% Detachment in one eye 0 detachment in both eyes Mean FU 14yr (1-27yr) In press “Ophthalmology” 2007 Summary: High Index of Suspicion 1. Neonatal myopia 2. Neonates with Pierre-Robin sequence or midline cleft. 3. Infants with spondyloepiphyseal dysplasia associated with myopia or deafness 4. Patients with a family history of rhegmatogenous retinal detachment 5. Sporadic cases of retinal detachment associated with joint hypermobility, midline clefting, or deafness Summary: Screening / Assessment 20% not myopic Cleft: subclinical Audiogram: DD conductive from sensorineural Radiology: hips, lumbar spine, knees Examine: Parents and siblings Remember “ocular-only” variants EUA: portable slit –lamp: gel, fundi, lens DNA 94% Mutation identified Richards et al (2006) Hum. Mutat. 27:696-704. Identification of Stickler syndrome complicated by double heterozygosity. Albright’s Hereditary Osteodystrophy (AHO): AD Mutations in the GNAS1 gene encoding Gs alpha protein. Part of a transducing protein complex that couples Parathyroid hormone short stature, obesity, round facies, subcutaneous ossifications, brachydactyly, skeletal abnormalities and mental retardation Treacher Collins syndrome: AD Disorder of craniofacial development caused by mutations in TCOF1. Expressed at the edges of the neural folds and the developing branchial arches Interference in the development of the first and second branchial arches Acknowledgements Clinical John Scott Annie McNinch Arabella Poulson Alan Ang Joss Herrtage John Yates Gill Whitmore Katherine Haslam David Baguley Audiology Dept. Philip Bearcroft Adrian Crisp Lindsay O’Shea Laboratory Allan Richards Maureen Laidlaw Sarah Meredith Sandy Goodburn Andrew Wyllie Barrie Harrison Bill Lee Mary McRae David Snead Funding The Evelyn Trust Action Medical Research Stanley Thomas Johnson Foundation Guide Dogs for the Blind Association The Isaac Newton Trust University of Cambridge Retinal Research Fund Stickler Syndrome Support Group