Radiographic and Tomographic Analysis in Patients with Stickler Syndrome Type I

Abstract

Objective: To further investigate the underlying pathology of axial and appendicular skeletal abnormalities such as painful spine stiffness, gait abnormalities, early onset osteoarthritis and patellar instability in patients with Stickler syndrome type I. Radiographic and tomographic analyses were organized.
Methods: From a series of Stickler syndrome patients followed from early life to late childhood. Ten patients (6 boys and four girls of different ethnic origins were consistent with the diagnosis of Stickler syndrome type I ). Phenotypic characterization was the baseline tool applied for all patients and genotypic correlation was performed on four families
Results: A constellation of axial abnormalities namely; anterolateral ossification of the anterior longitudinal spinal ligament with subsequent fusion of two cervical vertebrae, early onset Forestier disease (progressive spinal hyperostosis with subsequent vertebral fusion on top of bridging osteophytes and “Bamboo-like spine” resembling ankylosing spondylitis) and severe premature spine degeneration were evident. Appendicular abnormalities in connection with generalized epiphyseal dysplasia were the underlying aetiology in patients with Intoeing gait and femoral anteversion, early onset severe osteoarthritis of the weight bearing joint. Remarkable trochleo-patellar dysplasia secondary to severe osteoarthritis causing effectively the development of patellar instability was additional pathology. Mutation of COL2A1 has been confirmed as the causative gene for Stickler syndrome type I
Conclusion: We concluded that conventional radiographs and the molecular determination of a COL2A1 in patients with (Stickler syndrome type I) are insufficient tools to explain the reasons behind the tremendous magnitude of axial and appendicular skeletal abnormalities. We were able to modify the criteria of the clinical phenotype as designated by Rose et al in accordance with the novel axial and appendicular criteria as emerged from within our current study.

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2013; 10(9):1250-1258. doi: 10.7150/ijms.4997
Research Paper
Radiographic and Tomographic Analysis in Patients with
Stickler Syndrome Type I
Ali Al Kaissi
1,2

, Farid Ben Chehida
3
, Rudolf Ganger
2
, Vladimir Kenis
4
, Shahin Zandieh
5
, Jochen G
Hofstaetter
2
, Klaus Klaushofer
1
, Franz Grill
2
1. Ludwig Boltzmann Institute of Osteology, at the Hanusch Hospital of WGKK and, AUVA Trauma Centre Meidling, First Medical De-
partment, Hanusch Hospital, Vienna, Austria.
2. Orthopaedic Hospital of Speising, Paediatric Department, Vienna, Austria.
3. Institute of Radiology and Research -Ibn Zohr Centre of Radiology, Tunis, Tunisia.
4. Pediatric Orthopedic Institute n.a. H. Turner, Department of Foot and Ankle Surgery, Neuro-Orthopaedics and Systemic Disorders,
Saint-Petersburg, Russia.
5. Department of Radiology-Hanusch Hospital; Vienna, Austria.
 Corresponding author: Dr Ali Al Kaissi, Ludwig-Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Center Meidling,
First Medical Department, Hanusch Hospital Vienna, Austria. Email: ali.alkaissi@osteologie.at; ali.alkaissi@oss.at.
© Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/
licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
Received: 2012.08.07; Accepted: 2013.06.14; Published: 2013.08.03
Abstract
Objective: To further investigate the underlying pathology of axial and appendicular skeletal
abnormalities such as painful spine stiffness, gait abnormalities, early onset osteoarthritis and
patellar instability in patients with Stickler syndrome type I. Radiographic and tomographic
analyses were organized.
Methods: From a series of Stickler syndrome patients followed from early life to late childhood.
Ten patients (6 boys and four girls of different ethnic origins were consistent with the diagnosis of
Stickler syndrome type I ). Phenotypic characterization was the baseline tool applied for all patients
and genotypic correlation was performed on four families
Results: A constellation of axial abnormalities namely; anterolateral ossification of the anterior
longitudinal spinal ligament with subsequent fusion of two cervical vertebrae, early onset Forestier
disease (progressive spinal hyperostosis with subsequent vertebral fusion on top of bridging os-
teophytes and “Bamboo-like spine” resembling ankylosing spondylitis) and severe premature spine
degeneration were evident. Appendicular abnormalities in connection with generalized epiphyseal
dysplasia were the underlying aetiology in patients with Intoeing gait and femoral anteversion, early
onset severe osteoarthritis of the weight bearing joint. Remarkable trochleo-patellar dysplasia
secondary to severe osteoarthritis causing effectively the development of patellar instability was
additional pathology. Mutation of COL2A1 has been confirmed as the causative gene for Stickler
syndrome type I
Conclusion: We concluded that conventional radiographs and the molecular determination of a
COL2A1 in patients with (Stickler syndrome type I) are insufficient tools to explain the reasons
behind the tremendous magnitude of axial and appendicular skeletal abnormalities. We were able
to modify the criteria of the clinical phenotype as designated by Rose et al in accordance with the
novel axial and appendicular criteria as emerged from within our current study.
Key words: Stickler syndrome type I; Mutation of COL2A1 gene; Premature spine degeneration;
Forestier disease; Intoeing gait; Osteoarthritis; Patellar instability; CT scan.
Introduction
Stickler syndrome, designated hereditary pro-
gressive arthro-ophthalmopathy, is an autosomal
dominant connective tissue dysplasia characterized
by flat midface, high myopia, retinal detachment,
Ivyspring
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1251
cataracts, hearing loss, arthropathy, and cleft palate
(or bifid uvula) and musculoskeletal abnormalities
[1,2,3]. Most patients are recognized in childhood if
they present with cleft palate or severe ocular findings
or have a positive family history. Approximately one
fourth has an open cleft palate, and other patients
have more subtle clefting (bifid ovula or submucus
clefts) [4-6]. High myopia generally develops in early
childhood and is associated with vitreous degenera-
tion and a predisposition to retinal detachment and
cataracts (excepting patients with type 2 or non-ocular
Stickler syndrome). Stickler syndrome patients are
usually tall and slender. The genetic defect in Stickler
syndrome has highly variable phenotypic manifesta-
tions. There is a great diversity and severity of path-
ologic vitreous phenotype in association with Stickler
syndrome [3,7]. Nearly all patients have evidence of
mild spondyloepiphyseal dysplasia with frequent
spinal abnormalities (scoliosis, Scheuremann-like
kyphotic deformities, and spondylolisthesis) [8].
Premature osteoarthritis is common in Stickler syn-
drome, and there appears to be a predisposition to
femoral head complications (Legg-Perthes like disease
or slipped epiphysis), osteochondritis dissecans, Os-
good Schlatter disease, protrusio acetabuli, slipped
epiphyses, chondro-lysis, and osteopenia [9-12]. For-
estier disease (diffuse skeletal hyperostosis) is a
well-known radiographic diagnosis, usually seen in
patients with abnormal metabolic parameters such as
diabetes mellitus, hypercholesterolemia, hyperu-
ricaimia and others [13,14].
Intoeing is a frequent gait problem, usually en-
countered in children
with cerebral palsy [15-18].
Patients with symptomatic patellar instability
will have either
objective patellar instability (true at-
raumatic dislocation
with an anatomical abnormality)
or potential patellar instability
(pain, catching or
locking of the patellofemoral joint and inability
to
rehabilitate quadriceps with an anatomical abnormal-
ity) [19]. In this paper we described the importance of
comprehensive radiological and tomographic analysis
of the various axial and appendicular abnormalities in
patients with Stickler syndrome type I in order to
further manage these patients properly.
Materials and methods
The study protocol was approved by the Medical
University of Vienna (Ethics committee, EK Nr:
921/2009). Informed consents were obtained from the
patients guardians. The original material comprised
ten patients (six boys and four girls of different ethnic
origins) evaluated between 2002 and 2011 at the Or-
thopaedic Hospital of Speising, department of “Bone
Genetics”, Vienna, Austria. The mean age was 8 years
(range 1-19 years) and the mean age of first diagnosis
was 4.7 years (range 1- 12 years). The diagnosis of
Stickler syndrome type I was based on the details of
the phenotype affecting the ocular, craniofacial, au-
ditory, and musculoskeletal systems and highlighted
by the intra-and inter-familial variability. Most pa-
tients are recognized in childhood if they present with
cleft palate or severe ocular findings or have a positive
family history. We modified the diagnostic criteria for
type I Stickler syndrome as proposed by Rose et al
[11] on the basis of our novel findings of the appen-
dicular and axial skeletal systems.
Phenotypic characterization and conventional
radiographs was the initial tool of assessment and
diagnosis, followed by genotypic correlation in four
families of our series (table 1). Computed tomography
(CT scan) was the modality of choice. Patients were,
thereafter, divided into three distinctive groups.
Group 1 included patients with early onset
painful back stiffness. Some of the subjects in this
group have been further investigated by means of
reformatted CT scan to understand the etiology be-
hind their early onset spine stiffness. Five children
with the mean age of 7-19 have been identified be-
cause of generalized spine stiffness. Classically, the
pathophysiology of the spinal abnormalities in Stick-
ler syndrome has not been fully defined. Some re-
searchers explained the spine pathology in patients
with Stickler syndrome as it is because of the fibrillar
collagen mutations associated with the syndrome
(COL2A1, COL11A1, and COL11A2). Their beliefs
were based on that the malformation is due to weak-
ening of the intervertebral disks and the vertebral end
plates [8,9].
Group 2 included patients with abnormal gait
(Intoeing gait and femoral anteversion). Several re-
ports in the literature have attributed the internal
ro-
tation and the intoeing gait as a common feature in
patients with cerebral palsy because of spastic medial
hamstrings and the adductors and to spastic gluteus
medius and
minimus muscles [15-18].
Two male patients of 13 and 19 years respec-
tively presented with gait abnormalities (intoeing gait
and femoral anteversion) were further investigated
via CT scanning.
Group 3 included patients presented with early
onset severe osteoarthritis (We considered a patient to
have osteoarthritis on radiograph of the hip or knee, if
the score was 2 or higher in accordance with
Kellgren-Lawrence scoring system (seven patients
were included in this group). Radiographs in this re-
spect were able to directly visualized osseous features
of osteoarthritis, including marginal osteophytes and
subchondral sclerosis. Joint space assessment on ra-
diographs and sky-line images was found to be relia-
ble for evaluating the anatomic severity of osteoar-

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1252
thritis. Patients in this group manifested pain along
the weight bearing joints which get relatively less by
taking non-steroidal anti-inflammatory medications.
Measurements of the Kellgren and Lawrence score to
quantify osteoarthritis of the hip and knee have been
applied [20]. Also patients with patella-trochlear dys-
plasia secondary to severe osteoarthritis instability
were included (patellar stability is defined as it relies
on the limb alignment, the osseous architecture of the
patella and the trochlea, the integrity of the soft tissue
constraints, and the interplay of the surrounding
muscles) [21]. This subgroup of patients was assessed
by conventional radiographs and by CT scanning.
Table 1. summarizes the phenotypic characterization of Stickler syndrome type I in our patients as designated by Rose et al [11] and
modified by Al Kaissi et al.
Pa-
tients
age
year
Phenotyp-
ic-Genotypic
correlation
Cleft pal-
ate/Bifid
ovula
Ocular
abnormali-
ties
Auditory
abnormalities
Spine
Scolio-
sis/Kyphos
is
Scheuer-
mann-like
deformities
Early
onset
oteoar-
thritis
Gait abnor-
malities
Patellar
instability
Pateint
I
1
Phenotypic
and mutation
of COL2A1
Pierre-Rob
in se-
qunece
Congenital
glaucoma
Hypermobile
tympanic
membrane
Platyspon-
dyly
Thoracic
kyphosis
+++
-
-
-
Pateint
II
5
Phenotypic
characteriza-
tion
Cleft pal-
ate
Myopia &
astigma-
tism
Hypermobile
tympanic
membrane
Platyspon-
dyly
Thoracic
kyphosis
+++
-
Waddling
-
Patient
III
5
Phenotypic
characteriza-
tion
Cleft pal-
ate
Myopia
Conductive
hearling loss
Platyspon-
dyly
Scoliosis
+
-
-
-
Patient
IV
7
Phenotypic
characteriza-
tion
Cleft pal-
ate
Myopia
Conductive
hearling loss
Platyspon-
dyly
Scoliosis
+
++
Waddling
+
Patient
V
9
Phenotypic
and mutation
of COL2A1
Cleft pal-
ate
Myopia
Hypermobile
tympanic
membrane
Platyspon-
dyly-Giant
bridging
osteophytes
Kyphosis
+++
+++
Stooped posi-
tion and cal-
caneovalgus
deformity of
the ankles and
marked oste-
oporosis
Patel-
lo-trochle
ar dyspla-
sia
Patient
VI
13
Phenotypic
characteriza-
tion
Bifid ovu-
la
Myopia &
astigma-
tism
Conductive
hearling loss
Platyspon-
dyly
-
-
+++
Intoeing gait
Patel-
lo-trochle
ar dyspla-
sia
Patient
VII
13
Phenotypic
characteriza-
tion
Cleft pal-
ate
Myopia
-
onset senile
hyperostosis
(Forsteir
disease)
Kyphosis
+++
+++
Intoing gait
+++
Patient
VIII
15
Phenotypic
and mutation
of COL2A1
Cleft pal-
ate
Myopia and
family
history of
retinal
detachment
Conductive
hearling loss
Bamboo-like
spine
Scoliosis
-
+++
Stooped posi-
tion
+++
Patient
IX
17
Phenotypic
Bifid ovu-
la
Myopia and
family
history of
retinal
detachment
Hearing loss
Giant bridg-
ing osteophyt
Scoliosis
-
+++
Waddling gait
+++
Patient
X
19
Phenotypic
and mutation
of COL2A1
Cleft pal-
ate
Myopia -15
diopters
Conductive
hearling loss
Platyspon-
dyly and
early onset
senile hyper-
ostosis
(Forsteir
disease)
Scoliosis
-
+++
Stooped posi-
tion
+++

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Results
Group 1: Progressive spinal hyperostosis (For-
estier disease) secondary to ossification of the anterior
longitudinal spinal ligament associated with bridging
osteophytosis were the main pathological processes
behind the development of stiff and painful back bone
in these patients. Forestier disease (diffuse skeletal
hyperostosis) is a well-known radiographic diagnosis,
usually seen in patients with abnormal metabolic pa-
rameters such as diabetes mellitus, hypercholester-
olemia, hyperuricaimia and others. The condition is a
systemic, non-inflammatory disorder. Ossification
starts and extends from the insertions of skeletal
muscles, ligaments, and joint capsules [13,14].
Reformatted CT scan of the cervical spine in a
13-year-old girl showed anterolateral ossification of
the anterior longitudinal spinal ligament (Forestier
–like disease) with subsequent development of fu-
sion-like abnormality (fig 1).
Sagittal reformatted spinal CT scan in a 9-year
old boy showed, platyspondyly, extensive endplate
sclerosis and anterior spurring and severe irregulari-
ties/fragmentations of the anterior and the posterior
end-plates respectively associated with giant (bridg-
ing) osteophytes formation and Schmorl´s nodes
overwhelmed by severe premature degeneration as-
sociated with narrowing of the intervertebral disc
spaces. Note vertebral scalloping of the posterior
vertebral wall along the lower lumbar vertebrae (ar-
rows) (fig 2).
3D reformatted coronal CT scanning in a
15-year-old girl showed extensive hyperostosis of the
anterior longitudinal spinal ligaments, resulting in the
characteristic radiographic finding of a Bamboo-like
spine resembling ankylosing spondylitis, the overall
spine pathology is compatible with severe premature
spine degeneration overwhelmed by diffuse hyper-
ostosis (fig 3).
These children showed negative rheumatologic
parameters and their HLA-B27 was negative as well.
It was important to us, to differentiate vertebral fusion
in connection with early onset spinal hyperostosis
from the congenital form of block vertebrae as seen in
Klippel-Feil syndrome.
Group 2: Patients showed excessive femoral an-
teversion of the hips secondary to significant acetab-
ulo-femoral dysplasia (IR-internal rotation: 90 de-
grees, ER-external rotation: 30 degrees). We measured
the torsion of the femur by means of CT scan. There
was femoral anteversion of right hip of 38° and of the
left hip of 45 ° respectively in a 13-year-old-boy (fig 4).
CT scan to measure the rotation of the knees showed
internal rotation 7° of the right knee and 20° rotation
of the left knee in connection with trochlear dysplasia
(fig 5).
Group 3: To further delineate the joint patholo-
gy; Anteroposterior pelvis radiograph showed sig-
nificant epiphyseal dysplasia associated with exten-
sive fragmentation in a 19-year-old girl. This patient
showed severe osteoarthritis (defined as the presence
of hip pain and radiographic features of marked de-
generative changes using Kellgren-Lawrence scoring
system). The grade of osteoarthritis in these children
was compatible with grade 3 of Kellgren-Lawrence
score. Large osteophytes associated with marked
narrowing of the joint spaces, sclerosis and subse-
quent deformity of the bony contour, coxa valga and
osteopenia were present (fig 6).
Patellar instability has been referred to patel-
lo-trochlear dysplasia (anterior knee pain associated
with patellar instability) in connection with joint hy-
permobility and epiphyseal dysplasia has been en-
countered in all patients. Lateral knee radiograph
showed trochlear dysplasia, including the crossing
sign, supratrochlear spur, and double contour (a hy-
poplastic medial facet) associated with patellar dys-
plasia and patellar maltracking in a 9-year-old patient
(fig 7). The skyline view in female patient aged
17-years-old showed mal- tracking of the patella with
trochlear dysplasia associated with severe hyperpres-
sion of the patello- femoral joint, with subchondral
degenerative changes (this is a common feature in
patients with patellar instability in connection with
patello-trochlear dysplasia associated with profound
femoral notching), also, this is compatible with oste-
oarthritis of the patella-femoral joint (fig 8).
Sky line-view in a male patient aged 19- years
showed bilateral and symmetrical trochlear hypo-
plasia (flattened trochlea) with subsequent develop-
ment of patellar instability (fig 9). Sky-line view in
a-7-year-old boy showed severe trochlear dysplasia
with subsequent patellar mal-tacking associated with
significant osteoporosis (fig 10).
A-9-year-old boy with Stickler syndrome type I
manifested premature osteoarthritis matching grade
II of Kellgren-Lawrence grading scale with marked
narrowing of the joint spaces associated with osteo-
porosis and coxa valga. Note the flattening of the
capital femoral epiphysis, valgus deformity of the
tibia, severe valgus of the ankle joint and calcane-
ovalgus deformity of both feet. Gradual deformity
correction by temporary hemiepiphysiodeses of the
proximal and distal medial epiphyses using 8 plates
was performed to realign the lower limbs and to ena-
ble the child to walk and to lessen pain (fig 11)
Laboratory investigations: All our patients un-
derwent a series of biochemical parameter assess-
ments. Serum and urinary oligosaccharides, muco-
polysaccharides, serum lactate, pyruvate, creatine

Int. J. Med. Sci. 2013, Vol. 10
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1254
phosphokinase, alkaline phosphatase, calcium,
phosphorus, and vitamin D metabolism and chro-
mosomal studies, all were within the normal range.
Hormonal investigations included thyroid hormones;
adrenocorticotropic hormone and growth hormone
were negative as well. Erythrocyte sedimentation rate
(ESR) was unremarkable and ranged between 10-15
mm/1
st
hour. Antinuclear antibody (ANA) and
rheumatoid factors (FR) were negative. Genetic tests
showed mutation of COL2A1 (this form of mutation is
usually the result of premature termination codons
and nonsense mediated decay resulting in haploin-
sufficiency of type II collagen), four families under-
went genetic tests.
Fig 1. Reformatted CT scan of the cervical spine in a 13-year-old girl
showed anterolateral ossification of the anterior longitudinal spinal (For-
estier disease) (arrow).
Fig 2. Sagittal reformatted spinal CT scan in a 9-year old boy showed,
platyspondyly, extensive endplate sclerosis and anterior spurring associ-
ated with giant osteophytes formation, and Schmorl´s nodes associated
with narrowing of the intervertebral disc spaces. Note the development of
vertebral scalloping along the lower lumbar vertebrae (arrows).
Fig 3. 3D reformatted coronal CT scanning in a 15-year-old girl showed
extensive hyperostosis of the anterior longitudinal spinal ligaments, re-
sulting in the characteristic radiographic finding of a Bamboo-like spine
resembling ankylosing spondylitis, the overall spine pathology is compatible
with severe premature spine degeneration overwhelmed by diffuse hy-
perostosis (arrows).
Fig 4. Axial hip CT scan showed femoral anteversion of the hips secondary
to significant acetabulo-femoral dysplasia (IR-internal rotation: 90 degrees,
ER-external rotation: 30 degrees). We measured the torsion of the femur
by means of CT scan. There was femoral anteversion of right hip of 38° and
of the left hip of 45 ° respectively in a 13-year-old-boy.
Fig 5. Axial CT scan of the knees showed internal rotation 7° of the right
knee and 20° rotation of the left knee, note the epiphyseal fragmentations
associated with trochlear dysplasia.

Int. J. Med. Sci. 2013, Vol. 10
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1255
Fig 6. Anteroposterior hip radiograph in a 19-year-old girl showed severe
osteoarthritis matching the grade III of Kellgren-Lawrence grading scale.
Note the flattened and dysplastic epiphyses associated with large osteo-
phytes with marked narrowing of the joint spaces, sclerosis and subse-
quent deformity of the bony contour, coxa valga and osteopenia.
Fig 7. Lateral knee radiograph showed trochlear dysplasia, including the
crossing sign, supratrochlear spur, and double contour (a hypoplastic
medial facet) associated with patellar dysplasia and patellar maltracking in a
9-year-old-patient.
Fig 8. Skyline view showed mal- tracking of the patella with trochlear
dysplasia and hyperpression of the patello- femoral joint, with subchondral
degenerative changes (this is a common feature in patients with patellar
instability in connection with patello-trochlear dysplasia). Also, this com-
patible with osteoarthritis of the patello- femoral joint in a 15-year-old
patient.
Fig 9. Sky line-view in patient showed bilateral and symmetrical trochlear
hypoplasia (flattened trochlea) with subsequent development of patellar
instability in a 19-year-old patient.
Fig 10. Sky-line view in a-7-year-old
boy showed severe patellar- trochlear
dysplasia with subsequent patellar
mal-tacking associated with significant
osteoporosis.
Fig 11. A-9-year-old boy with Stickler
syndrome type I manifested premature
osteoarthritis matching grade II of
Kellgren-Lawrence grading scale with
marked narrowing of the joint spaces
associated with marked osteoporosis
and coxa valga. Note the flattening of
the capital femoral epiphysis, valgus
deformity of the tibia, severe valgus of
the ankle joint and calcaneovalgus
deformity of both feet. Gradual de-
formity correction by temporary
hemiepiphysiodeses of the proximal
and distal medial epiphyses using 8
plates was performed to realign the
lower limbs and to enable the child to
walk and to lessen pain.

Int. J. Med. Sci. 2013, Vol. 10
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1256
Discussion
Stickler et al reported wide phenotypic variabil-
ity, which often resulted in delayed or missed diag-
nosis in many cases. Certain clinical findings, how-
ever, are consistent: 95% ocular problems (retinal de-
tachment in 60%, myopia in 90%, and blindness in
4%); 84% facial abnormalities (flat nose, small mandi-
ble, or cleft palate); 70% hearing loss; 90% degenera-
tive joint disease and pain. Stickler syndrome is an
autosomal dominant disease characterized by midfa-
cial flattening and variable disorders of vision, hear-
ing and articulation. There is great diversity and se-
verity of pathologic articular conditions in patients
with Stickler syndrome. Most patients are recognized
in childhood if they present with cleft palate or severe
ocular findings or have a positive family history. Ap-
proximately one fourth has an open cleft palate, and
other patients have more subtle clefting (bifid ovula
or submucus clefts) [1,2].
The pathophysiology of the spinal abnormalities
in Stickler syndrome has not been fully defined. Fi-
brillar collagen mutations associated with the syn-
drome (COL2A1, COL11A1, and COL11A2) presum-
ably lead to malformation and weakening of inter-
vertebral disks and vertebral end plates. Rose et al
assumed that the vertebral abnormality is probably a
result of abnormal vertebral growth with exacerbation
by premature degenerative changes in adulthood [8].
Rose et al [8] evaluated the thoracolumbar spi-
nal abnormalities in 53 patients from 24 families with
Stickler syndrome (age range, 1-70 years). They found
that 34% of patients had scoliosis, 74% endplate ab-
normalities, 64% Schmorl´s nodes, 43% platyspon-
dylia, and 43% Scheuremann-like kyphosis. Sixty
seven percent of patients and 85% of adults reported
chronic back pain. Endplate abnormalities and
Schmorl´s nodes, have been described in old-age
group of patients via conventional radiographs. In our
patients early onset spine stiffness and the profound
vertebral anatomical abnormalities were in connec-
tion with Forestier disease giant osteophytes for-
mation, extensive end-plate abnormalities and the
early development of Forestier disease.
Progressive spinal hyperostosis secondary to os-
sification of the anterior longitudinal spinal ligament
is a well-known radiographic diagnosis encountered
in older patients. The condition is a systemic,
non-inflammatory disorder. Ossification starts and
extends from the insertions of skeletal muscles, liga-
ments, and joint capsules. The most prominent fea-
tures of the disease appear on the spine as contiguous
formation of newly formed ectopic bone, along the
anterolateral aspect of the spine. The cause and
pathogenesis of this disease are still unknown [13,14].
Our patients manifested radiographic features
compatible with an unusually early onset hyperosto-
sis resembling Forestier disease [13] in that there was
ossification along the anterolateral aspects of the cer-
vical and the thoraco-lumbar spine. Interestingly, we
observed significant hyperostosis along the thoracic
spine mimicking a “Bamboo spine” seen in patients
with ankylosing spondylitis, however, our patients
showed negative rheumatologic results and normal
metabolic parameters. Moreover, they manifested
abnormal vertebral growth and the severe premature
degeneration was accompanied by severe erosions
and irregularities of the anterior end-plates associated
with eventual disc-space obliteration and fusions
overwhelmed by significant hyperostosis at different
spine levels.
Rose et al [9] reviewed the hip abnormalities on
59 patients from 25 families with Stickler syndrome.
Ten percent had protrusio acetabuli, 21% coxa valga,
and 34% of adults had hip osteoarthritis. Sixty-three
percent of all patients and 79% of adults had chronic
hip pain. Arthritic changes and adult age were asso-
ciated with hip pain in adult patients with all types of
Stickler syndrome. Our patients were selected among
the Pediatric group of Stickler syndrome type I only,
moreover adults have been excluded. Premature de-
generative changes have been adequately demon-
strated in our patients via conventional radiographs
and CT scanning. Al Kaissi et al [12] described the
correlation of severe undermineralization of the bone
matrix and the compromised mechanical competence
in a patient with Stickler syndrome type I. They, con-
cluded that the development of appendicular skeletal
abnormalities in Stickler syndrome (type I) were se-
quelae of poor anatomical arrangements at the epi-
metaphyseal junction. These results are consistent
with a state of organic bone matrix deficits. The di-
minished mineral deposition may be attributable to a
fundamental defect in bone development and miner-
alization that is related to the connective tissue dis-
order, which is a direct consequence of the presumed
genetic mutation in COL2A1 [12]. These conclusions
were found to be compatible with the genetic muta-
tions of COL2A1 in our patients.
Intoeing is one of the most common conditions
encountered in paediatric orthopaedic practice. It is
important to make a definite diagnosis to elicit the
underlying pathological process. In infants; the most
common cause is metatarsus adductus. When present
in the second year of life, intoeing is commonly due to
internal tibial torsion. After 3 years of age, this prob-
lem is usually due excessive femoral anteversion.
Intoeing is a frequent gait problem in children
with
cerebral palsy. Management is based on the under-
standing the causes and the natural course of the

Int. J. Med. Sci. 2013, Vol. 10
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1257
condition and the effectiveness of various treatment
modalities [15-18]. Tonnis and Heinecke have shown
that an increased or decreased femoral anteversion is
associated with degenerative hip joint disease without
giving further aetiological explanation [15].
In our patients femoral anteversion was corre-
lated with generalized epiphyseal dysplasia and
fragmentations along the capital femoral epiphyses,
the acetabulae and the inferior femoral/tibial epi-
physeal dysplasias were manifestations of Stickler
syndrome type I. Clear differentiation of skeletal
dysplasias from femoral anteversion and or other
hip/knee deformities requires careful phenotypic
interpretation and characterization. Therefore, it is
empirical to delineate the underlying pathology be-
cause the prognosis of skeletal dysplasias compared
with the several causations of hip deformities requires
prompt indication for a precise therapeutic interven-
tion is more guarded [18].
Patellar stability relies on the limb alignment, the
osseous architecture of the patella and the trochlea,
the integrity of the soft tissue constraints, and the in-
terplay of the surrounding muscles. Patellofemoral
dysplasia refers to a spectrum of anatomic abnormal-
ities leading to anterior knee pain frequently associ-
ated with varying degrees of patellar instability. Dis-
orders such as patellofemoral dysplasia, osteochon-
dritis dessicans, chondromalacia patella, osteoarthri-
tis, subluxation of the patella and dislocation of the
patella are usually causing cartilage damage [19]. Pa-
tellofemoral osteoarthritis is a frequent clinical diag-
nosis associated with disability and often independ-
ent of tibiofemoral disease. The manifestation of pa-
tellofemoral osteoarthritis across the articulating sur-
faces of the joint is disparate, the patella demonstrat-
ing more severe signs of degeneration at a younger
age or shorter time after injury compared with the
juxtaposed femoral groove. Investigation into this
disparity may hold crucial insights into the aetiology
of osteoarthritis [20].
Patello-trochlear dysplasia with subsequent pa-
tellar maltracking and instability was identified in
three patients. Previous reports described trochlear
dysplasia as an abnormality of the shape and depth of
the trochlear groove mainly in its proximal extent in
non-syndromic patients (this was defined radiolgi-
cally by Dejour et al on the basis of the crossing sign
“croisement” [21].
Our patients demonstrated the combination of
patellar instability, maltracking and severe early onset
osteoarthritis in correlation with severe trochlear
dysplasia. We believe that patellofemoral dysplasia
and patellofemoral osteoarthritis are typical manifes-
tations in association with dysplastic trochlea in pa-
tients with Stickler syndrome. The anlage of the pa-
tella starts to form as early as the sixth week of fetal
life by detachment from the anlage of the lower part
of the femur, which takes place proximal to the region
of the future joint and then descends by the third
month of fetal life and lies in the depression between
the future femoral condyles. The patellar instability in
our patients emerged in connection with severe
trochlear dysplasia. The latter should be differentiated
from the more common and better known nail patella
syndrome, ischio-pubic-patellar syndrome, Mei-
er-Gorlin syndrome, Genito-patellar syndrome, and
Coffin-Siris syndrome [22,23,24].
In summary
We emphasize the importance of proper phe-
notypic characterization of children who are consid-
ered as chronic clients at the departments of oph-
thalmology, rheumatology and or orthopedics. In
addition, the role of CT scanning in the investigation
of patients with skeletal dysplasias is fundamental to
improve our understanding of the underlying pa-
thology, and to comprehend the various stages of the
bone pathophysiology. We wish to stress, that bone is
a dynamic tissue, which throughout life, bone tissue is
continually being formed and resorbed. This remod-
eling and reorganization is notoriously unpredictable
mechanism, particularly in patients with connective
tissue disorders as in Stickler syndrome.
Acknowledgement
We wish to thank Prof. Franco Laccone Depart-
ment für Medizinische Genetik. Medizinische Uni-
versität, Vienna, Austria for performing the genetic
test. We also wish to thank Prof. Hassan Gharbi (
Chairman of the Institute of Radiology and Research -Ibn
Zohr Centre of Radiology, Tunis, Tunisia), for helping us
in organizing and covering the required investiga-
tions for three families.
Competing Interests
The authors have declared that no competing
interest exists.
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