Stickler syndrome. Geert Mortier, MD, PhD Center for Medical Genetics Ghent University Hospital Ghent, Belgium

Transcription

1 Stickler syndrome Geert Mortier, MD, PhD Center for Medical Genetics Ghent University Hospital Ghent, Belgium Third European Course in Clinical Dysmorphology Rome, November 20-21, 2009

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3 Stickler syndrome Features reported in the original paper OCULAR congenital severe myopia (8 to 18 diopters) spontaneous retinal detachments chorioretinal degeneration presenile cataracts OSTEOARTICULAR bony enlargement of joints at birth joint pain in childhood (after exercise) degenerative joint disease at an early age mild joint hypermobility OROFACIAL cleft palate

4 Stickler syndrome Features reported in the subsequent literature OCULAR congenital severe myopia (8 to 18 diopters) spontaneous retinal detachments chorioretinal degeneration presenile cataracts vitreous degeneration open angle glaucoma OSTEOARTICULAR bony enlargement of joints at birth joint pain in childhood (after exercise) degenerative joint disease at an early age mild joint hypermobility vertebral anomalies (scoliosis, wedging, endplate deformities) OROFACIAL cleft palate Pierre Robin sequence bifid uvula, submucous cleft flat face, low nasal bridge, small chin AUDITORY conductive hearing loss sensorineural hearing loss mixed hearing loss

5 Stickler syndrome Locus heterogeneity defines several types A) Autosomal dominant inheritance type 1 Stickler syndrome: COL2A1 type 2 Stickler syndrome: COL11A1 type 3 Stickler syndrome: COL11A2 B) Autosomal recessive inheritance type 4 (?) Stickler syndrome: COL9A1 Other loci??

6 Interaction between the collagens type II, IX, XI From Eyre DR, Weis MA, Wu JJ. Methods 2008; 45: 65-74

7 Type II collagen fibers are present in the cartilage and vitreous humor Cartilage matrix Cartilage Vitreous humor Eye Type II Type XI Type II Type XI Collagen Collagen Collagen Collagen COL2A1 COL11A1 COL2A1 COL11A1 COL11A2 COL5A2 COL2A1 COL2A1

8 Structure fibrillaire of fibrillar collagenen collagens procollagen chain 3 procollagen chains form a triple helical trimer collagen fiber

9 The formation of the triple helix starts at the C-terminus and proceeds towards the N-terminus N C

10 Stickler syndrome type 1 most frequent type of Stickler syndrome (1 in 5000 to ?) includes the original family reported by Stickler* autosomal dominant inheritance mainly loss-of-function mutations in COL2A1 intra- and interfamilial variability key features: - early-onset myopia - spontaneous retinal detachments - congenital type 1 (membranous) vitreous anomaly - cleft palate and Pierre-Robin sequence - midface hypoplasia - joint pain in childhood - early-onset osteoarthrosis - conductive or sensorineural hearing loss (mild; high tones) *Williams CJ et al. Am J Med Genet 1996;63:461

11 The family of type 2 collagen disorders Disproportionate short stature Normal stature Lethal conditions Short trunk dwarfism Early-onset osteoarthrosis - Achondrogenesis type 2 - Hypochondrogenesis - Platyspondylic dysplasia, Torrance type - Spondyloepiphyseal dysplasia congenita - Kniest dysplasia - SEMD Strüdwick type - Spondyloperipheral dysostosis - Stickler syndrome - Czech dysplasia metatarsal type - Avascular necrosis of the femoral head - Vitreoretinopathy with phalangeal epiphyseal dysplasia

12 Stickler syndrome type 1 Patient pictures

13 Study of genotype and phenotype in a large series of patients with Stickler syndrome type 1 Referral of DNA samples from 278 individuals ( ) 188 probands were included and had 2 of the following features: 90 probands excluded from the study myopia spontaneous retinal detachment cleft palate sensorineural hearing loss arthropathy insufficient clinical data other diagnosis 100 probands with a COL2A1 mutation Hoornaert et al. Submitted to Eur J Hum Genet

14 Mutation analysis of COL2A1 in a large series of Stickler syndrome patients 100 probands with a COL2A1 mutation panel of 77 different COL2A1 mutations include: 1 deletion of the entire gene 13 nonsense mutations 21 deletions 1 insertion 9 duplications 2 insertion/deletions 22 splice site alterations 1 synonymous mutation (creation of a cryptic splice site) 2 missense mutations (R565C;R904C) 5 missense mutations (G216D;G219R;G222V;G492D;G1131A) no hot spots in the COL2A1 gene 13 mutations observed in more than one proband 70/77 mutations are predicted to result in a loss of function

15 Frequency of features in patients with a COL2A1 mutation (n=100) and without a mutation (n=88) p-value < p-value < 0.005

16 Seven most discriminating features (with β-coefficients) as revealed by binary logistic regression analysis

17 # patients Overlap in total score between mutation positive and mutation negative group score

18 Box plot presentation of the total scores in both patient groups outlier max Q3 median 9 Q1 min

19 The presence of vitreoretinal anomalies and cleft palate are good indicators for Stickler syndrome type 1 Characteristics Score -retinal abnormalities 5 -positive family history 5 -vitreous abnormalities 4 -cleft palate 4 -retinal tear and/or detachment 3 -low nasal bridge 1 -micrognathia 1 Total score 23

20 Stickler syndrome type 2 * Marshall D. Am J Ophthalmol 1958;45:143 autosomal dominant inheritance mutations in COL11A1 (usually splice site mutations, intron 50 is hot spot) key features: - early-onset myopia - spontaneous retinal detachments - type 2 (beaded) vitreous anomaly (but type 1 anomaly also observed!) - cleft palate, Pierre Robin sequence - flat face, protruding eyes, hypertelorism, low nasal bridge - mild to severe early-onset sensorineural hearing loss - radiographic abnormalities more pronounced than in type 1 Stickler allelic with Marshall syndrome features in the original kindred*: - myopia, retinal detachment, fluid vitreous - hearing loss - ectodermal dysplasia (missing teeth, hypohidrosis) - short stature - distinctive face: hypertelorism, short nose, bulging eyes - thickening cranial vault; absence frontal sinuses

21 Stickler syndrome type 2 Majava M et al. Am J Med Genet 2007;143A:258

22 Patient pictures

23 COL2A1 COL11A1

24 Stickler syndrome type 3 rare type of Stickler syndrome (only a few cases reported) autosomal dominant inheritance mutations in COL11A2 (in frame deletions) key clinical features: - absence of ocular anomalies - cleft palate - sensorineural hearing loss - midface hypoplasia and upturned nose - arthropathy allelic with Weissenbacher-Zweymüller syndrome* - Pierre Robin anomaly - snub nose - normal stature - sensorineural hearing loss - normal eyes - dumbbell-shaped femora; coronal vertebral clefts (neonate) - enlarged epiphyses (most pronounced at 13 yrs) * Pihlajamaa T et al. Am J Med Genet 1998;80:115

25 Stickler syndrome type 4 rare form of Stickler syndrome (only one family reported*) autosomal recessive inheritance homozygous R295X mutation in COL9A1 key clinical features: - proportionate short stature - genua valga - joint pain - flat face - normal palate - moderate-to-severe sensorineural hearing loss - moderate-to-high myopia - vitreous changes (~ aged vitreous) - retinal anomalies (atrophic holes, pigmentary degeneration) - mild radiographic changes *Van Camp G et al. Am J Hum Genet 2006;79:449

26 Stickler syndrome type 4 patients unaffected flattened and irregular femoral epiphyses flattenend metacarpal epiphyses Moderate-to-severe SNHL with mildly down-sloping audiogram Van Camp G et al. Am J Hum Genet 2006;79:449

27 Stickler syndrome type 4 patients unaffected sibs Van Camp G et al. Am J Hum Genet 2006;79:449

28 Stickler syndrome Differential diagnosis Type 2 collagen disorders with short stature (Kniest, SEDC) - radiographs more affected; height is low normal in Stickler Czech dysplasia metatarsal type - short toes; no ocular and palatal involvement; R275C mutation in COL2A1 Marshall syndrome (?) - ectodermal dysplasia; skull xrays; facial dysmorphism OSMED - recessive condition; big epiphyses, platyspondyly; typical nose; short stature multiple epiphyseal dysplasia - degenerative joint disease without ocular and orofacial anomalies Wagner syndrome (Stickler syndrome with only ocular involvement does exist!) - different vitreoretinal phenotype; poor dark adaptation (night blindness) - mutations in CSPG2 (versican) conditions with cleft palate

29 Stickler syndrome Management repair of cleft palate; monitoring of feeding and respiratory problems annual evaluation by an ophthalmologist (starting in infancy) early detection of retinal tears, holes, detachment (cryotherapy and laser therapy) annual audiologic evaluations avoidance of obesity and competition/contact sports (to protect the joints and prevention of retinal detachments) joint replacement surgery