Morquio A:
Musculoskeletal
manifestations
Morquio A patients present with marked
musculoskeletal abnormalities
Skeletal dysplasia
– Spinal abnormalities
– Pectus carinatum
– Hip dysplasia
– Genu valgum
– Ankle valgus
– Hand abnormalities
– Flat facial features
– Mandibular protrusion
Short stature
Joint instability
Joint subluxation
Joint degeneration
Abnormal gait
Weak hand grip
Left image: Kalteis et al, Arthroscopy, 2005
Top and bottom right images: Atinga et al, J Bone Joint Surg Br, 2008
Musculoskeletal abnormalities are the most
common presenting features in Morquio A
% Subjects
100%
97%
94%
93%
93%
91%
87%
85%
83%
80%
71%
60%
40%
20%
0%
Pectus
carinatum
Abnormal gait
Short stature
n = 325 subjects
Data based on medical history reviews
MorCAP Baseline data
Harmatz et al, Mol Genet Metab, 2013
Genu valgum
Short neck
Joint laxity
Kyphoscoliosis
Joint
stiffness/pain
Hip dysplasia
Musculoskeletal abnormalities are the most common
presenting symptoms in Morquio A
Common initial presenting symptoms in Morquio A
n = 326 subjects
International Morquio A Registry
Montano et al, J Inherit Metab Dis, 2007
Morquio A disrupts normal development and
maturation of cartilage and bone
Articular cartilage is altered in Morquio A
patients:
– KS accumulation in chondrocytes
– Poorly organized tissue structure
– Increased Type I collagen and reduced
Type II collagen
– Thicker, irregularly shaped collagen fibrils
Articular cartilage chondrocyte in
(A) control, (B) Morquio A patient
Role of GAG-mediated inflammation?
– Identification of biomarkers is critical for
elucidation of pathogenesis
Collagen fibrils in articular cartilage
of (A) control, (B) Morquio A patient
Bank et al, Mol Genet Metab, 2009
Dvorak-Ewell et al, PLoS, 2010; Bank et al, Mol Genet Metab, 2009; De Franceschi et al, Osteoarthritis Cartilage, 2007;
Kalteis et al, Arthroscopy, 2005; McClure et al, Pathology, 1986
Key radiographic findings in Morquio A
Dysostosis multiplex
Spine:
Dens hypoplasia
Platyspondyly
Inferiorly beaked vertebral bodies
Posterior scalloping of vertebrae
Thoracolumbar kyphosis
Hips and lower extremities:
Rounded iliac wings
Acetabular dysplasia
Coxa valga
Genu valgum
Ankle valgus
Upper extremities:
Short, broad metacarpals
Proximal metacarpal rounding
Irregular/hypoplastic carpal bones
Thorax:
Pectus carinatum
Paddle-shaped ribs
Short, thick clavicles
(Findings vary and can be subtle)
Spine: Normal
Image courtesy of Ralph Lachman, MD
Spine: Dysostosis multiplex
Dens hypoplasia
Platyspondyly
Anterior beaking
Posterior scalloping
Thoracolumbar kyphosis
Solanki et al, J Inherit Metab Dis, 2013
Hips: Normal
Image courtesy of Ralph Lachman, MD
Hips and lower extremities: Dysostosis multiplex
8 year old Morquio A
Image courtesy of Ralph Lachman, MD
6 year old Morquio A
Image courtesy of Klane White, MD
White, Curr Orthop Prac, 2012
Rounded iliac wings
Underdeveloped acetabula
Dysplastic capital femoral epiphyses
Coxa valga
Genu valgum
Ankle valgus
Thorax: Normal
Image courtesy of Ralph Lachman, MD
Thorax: Dysostosis multiplex
Paddle-shaped ribs
Pectus carinatum
Short, thick clavices
8 year old Morquio A
Image courtesy of Christina Lampe, MD
Hands: Normal
Image courtesy of Ralph Lachman, MD
Hands: Dysostosis multiplex
Short, broad metacarpals
Proximal metacarpal rounding
Hypoplastic carpal ossification
8 year old Morquio A
Image courtesy of Ralph Lachman, MD
Short stature is a characteristic feature of Morquio A
Growth retardation in Morquio A
71% of Morquio A subjects ≤ 18 years are below 3rd percentile in height
Majority of adults are < 120 cm in height
n=325 Morquio A subjects
MorCAP baseline data
Harmatz et al, Mol Genet Metab, 2013; BioMarin data on file
Short stature is a characteristic feature of Morquio A
Growth retardation in Morquio A
International Morquio A registry
Montano et al, J Inherit Metab Dis, 2007
Joint abnormalities are common in Morquio A patients
Joint instability
– floppy wrists with weak grip and loss of
fine motor skills
– exacerbates knee valgus and gait
abnormalities
Subluxations of the hip and atlantoaxial
joints are common
Joint degeneration due to bone defects,
cartilage deterioration and altered mechanics
Joint pain
Atinga et al, J Bone Joint Surg Br, 2008
Harmatz et al, Mol Genet Metab, 2013; Aslam et al, JIMD Rep, 2013; Tomatsu et al, Curr Pharm Biotechnol, 2011;
Montano et al, J Inherit Metab Dis, 2007
Hand function is compromised
A study of 10 Morquio A patients (Aslam et al, 2012) revealed:
– Wrist instability in all subjects
 Average difference of 93 between active and passive
ROM at wrist joint
– Reduced hand grip strength in all subjects
– Difficulties with tasks requiring strength, e.g. lifting heavy
objects and pouring from a bottle
Of the 153 subjects ≥ 12 years of age in the MorCAP
baseline study (Harmatz et al, 2013):
Hand dysfunction contributes
significantly to difficulties
with activities of daily living
• 30% could not cut their fingernails
• 22% could not tuck in shirts
• 22% were unable to open jars
• 20% were unable to tie shoelaces
Aslam et al, JIMD Rep, 2013; Harmatz et al, Mol Genet Metab, 2013; BioMarin data on file
Abnormal gait results from bone and joint defects
A study of 9 children with Morquio (subtype not specified) with no previous lower
extremity surgery revealed a consistent gait pattern:
– Slower walking speed, reduced cadence and reduced stride length vs normal
– Trunk, pelvis, hip: increased forward tilt of trunk and pelvis, increased hip flexion
– Knee: increased knee flexion, genu valgus, and external tibial torsion; dynamic
knee varus-valgus joint laxity
– Joint moments and power: reduced hip and ankle joint moments, reduced
power generation
Embed Dawn video (Youtube)
http://www.youtube.com/watch?v=ugeVScsV0oM
Dhawale et al, J Pediatr Orthop B, 2012
Orthopedic management of the spine, hips and lower
extremities is essential for optimal patient outcomes
Cervical instability, spinal stenosis and
spinal cord compression are common in
Morquio A. Early diagnosis and timely
intervention can reduce the risk of myelopathy,
quadriparesis and death.
Solanki et al, J Inherit Metab Dis, 2013
At 4 years old
At 7 years old
Progressive genu valgum and hip deformity in
Morquio A. Surgical correction can improve
mechanics, increase walking ability and endurance,
reduce pain, and delay onset of arthritis.
Radiographs from Dhawale et al, J Pediatr Orthop
B, 2012
Solanki et al, J Inherit Metab Dis, 2013; Dhawale et al, J Pediatr Orthop B, 2012; White, Rheumatology, 2011; White,
Curr Orthop Prac, 2012
Regular assessments of the spine
are recommended for improved patient outcomes
Assessment
At diagnosis
Frequency
Neurological exam
Yes
6 months
Plain radiography cervical spine (AP,
lateral neutral and flexion-extension)
Yes
2-3 years
Plain radiography spine (AP, lateral
thoracolumbar)
Yes
2-3 years if evidence
of kyphosis
or scoliosis
MRI neutral position, whole spine
Yes
1 year
Flexion-extension of cervical spine by
MRI
Yes
1-3 years
CT neutral region of interest
Solanki et al, J Inherit Metab Dis, 2013
Preoperative planning
Surgical interventions
Indications include:
– Neurological deficits + instability
– Cord compression with signal change on MRI
Ain et al, Spine, 2006
Cervical spine:
– Posterior fusion for C1-C2 subluxation and
instability, often with posterior occipito-cervical
fixation
– If subluxation is irreducible and cord compression is
present, decompression + fusion is indicated
– Prophylatic fusion recommended by some
Thoracolumbar kyphosis:
– Decompression, segmental instrumentation and
fusion
– Anterior discectomy and fusion strongly
recommended to augment posterior fusion in cases
of rigid kyphosis
Image courtesy of Klane White, MD
White, Curr Orthop Prac, 2012
Solanki et al, J Inherit Metab Dis, 2013; White, Curr Orthop Prac, 2012; Ain et al, Spine (Phila PA 1976), 2006;
Ransford et al, J Bone Joint Surg Br, 1996; Lipson, J Bone Joint Surg Am, 1977
Outcomes of spine surgery
Short-term post-operative outcomes generally good
Possible post-surgical complications:
– Late instability below fusion site may necessitate
multiple fusions
– Halo pin tract infection
→ Long-term monitoring is important
Long-term outcomes beyond 5 years are less known
– few studies
Morquio patient 26 years post-surgery:
complete resolution of quadriparesis achieved
and neurological function maintained 26 years
after C1-C2 decompression and stabilization
Image courtesy of Klane White, MD
White, J Bone Joint Surg Am, 2009
Solanki et al, J Inherit Metab Dis, 2013; White, J Bone Joint Surg Am, 2009; Ain et al, Spine (Phila PA 1976), 2006; Dalvie et al, J Pediatr
Orthop B, 2001; Holte et al, Neuro-Orthopedics,1994; Houten et al, Pediatr Neurosurg, 2011; Lipson, J Bone Joint Surg Am, 1977; Ransford
et al, J Bone Joint Surg Br, 1996; Stevens et al, J Bone Joint Surg Br 1991; Svensson and Aaro, Act Orthop Scand, 1988.
Regular assessments of the hips and lower
extremities are recommended for optimal outcomes
Initial
assessment
Annually
Hips/pelvis: AP pelvis radiograph
X
X
Lower extremities:
Standing AP radiographs
X
Assessment
White, Rheumatology, 2011
As
clinically
indicated
X
Hip deformity correction and outcomes
Pelvic osteotomy + femoral osteotomy
– Hip subluxation may recur
– Shelf acetabuloplasty + femoral varus derotation osteotomy (VDRO)
reported to yield good outcomes with no recurrent hip subluxation
Total hip arthroplasty
Morquio A patient with hip subluxation: (A) At 12.5
years underwent Pemberton osteotomy + VDRO. (B) At
16 years, hip subluxation recurred. (C) At 18 years, hips
well located 2 years post-shelf acetabuloplasty
Morquio adult: satisfactory bilateral
hip replacement, 7 year followup
Dhawale et al, J Pediatr Orthop, 2012
Lewis et al, J Bone Joint Surg Br, 2010
Dhawale et al, J Pediatr Orthop, 2012; Tassanari et al, Chir Organi Mov , 2008; Lewis et al, J Bone Joint Surg Br, 2010;
White, Curr Orthop Prac, 2012
Knee deformity correction and outcomes
Guided growth for younger patients with mild to
moderate genu valgum
Osteotomy for patients with limited growth potential
and severe genu valgum
Recurrence after genu valgum correction is common
Total knee arthroplasty for patients with advanced
arthrosis
Morquio A adult, 4 years after total knee arthroplasty
Hemiepiphysiodesis (F) of
proximal tibia and distal
femur with 8 plates in 10 year
old Morquio A patient. (G)
Maintenance of correction 1
year after removal of 8 plates,
at age 13 years. Patient also
underwent guided growth for
ankle valgus.
de Waal Malefijt et al. Arch Orthop Trauma Surg, 2000
Dhawale et al, J Pediatr Orthop, 2012
Dhawale et al, J Pediatr Orthop, 2012; de Waal Malefijt et al. Arch Orthop Trauma Surg, 2000; Atinga et al, J Bone Joint Surg Br,
2008; White, Curr Orthop Prac, 2012
Airway and anesthetic management of Morquio A
patients presenting for surgery is challenging
Morquio A patients are at high risk of anesthesia-related morbidity and mortality
due to:
– Cervical instability and myelopathy
– Compromised respiratory function
 Upper and lower airway obstruction
 Restrictive lung disease
– Cardiac abnormalities
Any elective surgery requires:
– Thorough pre-operative ENT, pulmonary and cardiac evaluations
– Pre-operative radiological assessment of the cervical spine
– Skilled personnel in airway management
– Spectrum of airway management equipment
Morquio A patients should be managed by experienced anesthesiologists at
centers familiar with MPS disorders
Theroux et al, Paediatr Anaesth, 2012; Solanki et al, J Inherit Metab Dis, 2013; Walker et al, J Inherit Metab Dis, 2013;
McLaughlin et al, BMC Anesthesiol, 2010; Morgan et al, Paediatr Anaesth, 2002; Shinhar et al, Arch Otolaryngol Head Neck Surg, 2004;
Belani et al, J Ped Surg, 1993; Walker et al, Anaesthesia, 1994
Non-surgical interventions
Physical therapy
Walker/wheelchair use
Pain management
MorCAP baseline data (Harmatz et al, 2013)
revealed:
• 49% of 300 Morquio A subjects required
wheelchairs (mean age= 14.5 years)
• 26% of 298 Morquio A subjects used walking
aids (mean age= 14.5 years)
Harmatz et al, Mol Genet Metab, 2013