Center for Medical Genetics - Istituti

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

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

OCULAR
OROFACIAL
Stickler syndrome
Features reported in the subsequent literature
• congenital severe myopia (8 to 18 diopters)
• spontaneous retinal detachments
• chorioretinal degeneration
• presenile cataracts
• vitreous degeneration
• open angle glaucoma
• cleft palate
• Pierre Robin sequence
• bifid uvula, submucous cleft
• flat face, low nasal bridge, small chin
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)
AUDITORY
• conductive hearing loss
• sensorineural hearing loss
• mixed hearing loss

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??

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

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

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

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

Stickler syndrome type 1
• most frequent type of Stickler syndrome (1 in 5000 to 10.000 ?)
• 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

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

Stickler syndrome type 1
Patient pictures

Study of genotype and phenotype in a large series
of patients with Stickler syndrome type 1
Referral of DNA samples from 278 individuals (1997-2007)
188 probands were included
and had ≥ 2 of the following features:
• myopia
• spontaneous retinal detachment
• cleft palate
• sensorineural hearing loss
• arthropathy
100 probands with a COL2A1 mutation
90 probands excluded
from the study
• insufficient clinical data
• other diagnosis
Hoornaert et al. Submitted to Eur J Hum Genet

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

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

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

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

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

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

Stickler syndrome type 2
• 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
* Marshall D. Am J Ophthalmol 1958;45:143

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

Patient pictures

COL2A1 COL11A1

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

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

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

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

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

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